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Carbonic anhydrase (CA) is an ancient family of zinc metalloenzymes present in almost all organisms. All CAs can be grouped into 3 broad classes (α, β, and γ), which have evolved independently and also vary widely in sequence and overall folding.<br />CA9, a member of the alpha class, is a plasma membrane protein with a catalytic domain in the extracellular space. Its expression is restricted to very few healthy tissues (mainly the gastrointestinal tract). CA9 expression is strongly induced by hypoxia and can be downregulated by wild-type von Hippel–Lindau (VHL) tumor suppressor protein. CA9 expression is elevated in many types of tumors, especially solid hypoxic tumors that do not respond well to conventional radiation and/or chemotherapy; CA9 is considered a marker of tumor hypoxia and a promising target for cancer therapeutic intervention.